Chronic renal disease is a world-wide problem. In the United States, there were over 400,000 patients enrolled in Medicare-funded end-stage renal disease programs at the end of 2002. It is projected that by 2010, more than 650,000 patients will be enrolled in such programs, at a cost of over $28 billion a year. In spite of improvements in dialysis therapy, patients often experience a decline in quality of life. Mortality and morbidity continue to be significant.
Renal failure is associated with an inability of the kidneys to excrete large loads of electrolytes and other substances. As a result, patients often experience generalized edema, acidosis, high concentration of non-protein nitrogen compounds, especially urea, and high concentrations of other urinary retention products including creatinine. This condition is known as uremia.
Chronic kidney disease also is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome. In fact, atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality in end-stage renal disease (ESRD) patients. In many cases, ESRD patients also do not respond to erythrorpoietin therapy employed to manage their anemia.
It is well established that ESRD is a state of chronic systemic inflammation. The kidney is an organ that not only excretes cytokine metabolites but also contributes to cytokine production through its endocrinal function. It has been reported that the kidney may play a role in handling the clearance of pro-inflammatory cytokines. Even mild to moderate reduction in glomerular filtration rate appears to result in increased levels of circulating pro-inflammatory cytokines.
The hemodialysis procedure itself contributes to an inflammatory response and mortality in dialysis patients is higher than that in the general population across all age groups. Hemodialysis patients suffer from chronic inflammation for reasons such as potential blood contamination from endotoxin in the dialysis fluid, repeated contact of blood with artificial materials in the extracorporeal circuit, infections related to vascular access problems and so forth.
An approach for the non-specific elimination of circulating cytokines by continuous renal replacement therapies (CRRT) was proposed but reported controversial. In addition, it was found that treatment with oral pentoxyfilline could reduce T-cell expression of TNF-α and IFN-γ. The use of steroids, thalidomide, anti-thymocyte globulin, anti-lymphocyte globulin and of the anti-CD3 monoclonal antibody OKT3 has been suggested. Inhibitors of TNF-α have been approved by the U.S. FDA as therapies for patients with various autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis and Crohn's disease; their use in systemic inflammatory response syndrome (SIRS) and for reversing the inflammatory process in erythropoietic resistance has been suggested. IL-1 receptor antagonist has been approved by U.S. FDA to treat rheumatoid arthritis and anti-IL-6 receptor antibody has been tested in patients with rheumatoid arthritis with good results. In addition, a humanized monoclonal antibody to IFN-γ is now in clinical testing for the treatment of Crohn's disease.